Diabetes mellitus is a metabolic disorder characterized by the failure of body tissues to store carbohydrates at the normal rate. Resistance to the action of insulin is the most important factor to type II diabetes. When this resistance exceeds the capacity of the beta cells to produce insulin, a person becomes diabetic. During the last 70 years people suffering from diabetes have been greatly aided by receiving controlled amounts of insulin.
Obesity, particularly upper body obesity, is often associated with non-insulin-dependent diabetes mellitus (NIDDM). These so called type II diabetics do not have an absolute requirement for insulin as their beta cells are able to secrete insulin, albeit often at diminished levels. In addition such patients are often obese and may demonstrate an inability to respond to insulin.
It is well known that a regimen of diet and exercise leading to weight loss is the best approach for treating obese type II diabetics. Unfortunately, these regimens are usually unsuccessful. Failure to loss weight may be due to genetically inherited factors that contribute to increased appetite, a preference for high calorie foods, reduced physical activity, and an increased lipogenic metabolism. People inheriting such genetic predispositions are prone to obesity and often become type II diabetics, regardless of their efforts to combat the condition.
The ob/ob mouse is a model of obesity and diabetes that is known to carry an autosomal recessive trait linked to a mutation in the sixth chromosome. Yiying Zhang and co-workers published the positional cloning of the mouse gene (ob) linked with this condition. Yiying Zhang et al. Nature 372: 425-32 (1994). This report disclosed a gene coding for a 167 amino acid protein (hereinafter leptin) with a 21 amino acid signal peptide that is exclusively expressed in adipose tissue.
Physiologists have postulated for years that, when a mammal overeats, the resulting excess fat signals to the brain that the body is obese which, in turn, causes the body to eat less and burn more fuel. G. R. Hervey, Nature (London), 227:629-631 (1969). This model of feedback inhibition is supported by parabiotic experiments, which implicate a circulating hormone controlling adiposity.
Based on recent in vivo experiments conducted under the inventor's supervision, leptin has now been shown to be an adiposity regulating hormone. Most importantly however, blood parameters monitored during these experiments quite unexpectedly demonstrated that treatment with leptin totally ameliorated the diabetic state of the research animals.
Moreover, circulating levels of leptin in obese individuals have been shown to vary widely. Consequently, it is now believed that certain subpopulations of obese type II diabetics are particularly amenable to treatment with leptin. Pharmacological agents which are biologically active and mimic the activity of leptin are therefore useful for treating obese type II diabetics, particularly those with abnormal levels of circulating leptin.